The present invention relates to a method for treating and/or preventing obesity (especially abdominal obesity), and to treating or suppressing the acquisition of abnormal insulin resistance, in susceptible warm-blooded animals including humans. The methods involve administering compounds of the general formula I below, or their pharmaceutical compositions. In other embodiments, the methods involve administering a selective estrogen receptor modulator.(xe2x80x9cSERMxe2x80x9d) in combination with a sex steroid precursor.
Obesity, a condition characterized by excessive bodily fat, is a well known risk factor for many diseases such as cardiovascular diseases, hypertension, diabetes and breast cancer. Moreover, personal appearance plays an important part in the overall well-being of most people.
Common treatments of obesity such as various diets (including food restriction diets), weight loss programs and exercise give varying degrees of success for many people. However, there remains a need for other techniques for those who experience insufficient results with prior art techniques, or for use as a supplement to prior art techniques.
Recently, some estrogen agonists/antagonists were disclosed for the treatment or prevention of obesity: Raloxifene and related compounds in European Patent Application Number EP 0 659 423 A1; estrogen agonists having a benzothiophene nucleus in European Patent Application Number EP 0 716 855 A2 ; 3,4-diphenyl chromans in International Application Number PCT/DK96/00011; naphtyl estrogen agonist/antagonist in International Application Number PCT/IB95/00286.
It was also reported that Tamoxifen, another estrogen agonist/antagonist, prevents sulpiride-induced weight gain in female rats (Baptista et al., Pharmacol., Biochem. Behav. (1997), 57(1/2), 215-222). It is also reported that Tamoxifen mimics the effect of estradiol on food intake, body weight and body composition in rats (Wade et al., American Journal of Physiology 1993, 33(6), R1219-1223.)
DHEA has also beneficial effects in the treatment and/or prevention of obesity. In aged Sprague-Dawley rats, Schwartz (in Kent, Geriatrics 37: 157-160, 1982) has observed that body weight was reduced from 600 to 550 g by DHEA without affecting food intake. Schwartz (Cancer 39: 1129-1132, 1979) observed that C3H mice given DHEA (450 mg/kg, 3 times a week) gained significantly less weight and grew older than the control animals, had less body fat and were more active. The reduction in body weight was achieved without loss of appetite or food restriction. Furthermore, DHEA could prevent weight gain in animals bred to become obese in adulthood (in Kent, Geriatrics 37: 157-160, 1982).
DHEA administration to lean Zucher rats decreased body weight gain despite increased food intake. Treated animals had smaller fat pads thus, overall, suggesting that DHEA increases food metabolism, resulting in lower weight gain and fat accumulation (Svec et al., Proc. 2nd Int. Conf. Cortisol and Anti-Cortisols, Las Vegas, Nev., USA, p. 56 abst., 1997).
Obesity was found to be improved in the Avy mutant mouse (Yen et al., Lipids 12: 409-413, 1977) and in the Zucker rat (Cleary and Zisk, Fed. Proc. 42: 536, 1983). DHEA-treated C3H mice had a younger appearance than controls (Schwartz, Cancer Res. 39: 1129-1132, 1979).
Abdominal fat has been associated with metabolic risk factors for coronary breast disease (Imbault et al. Metabolism 1999, 48 (3), 355-62; Ledoux et al. (CMAJ 1997, 157 Suppl.1; 46-53).
It is accordingly an object of the present invention to reduce adipose tissue, especially abdominal fat.
It is another object of the present invention to reduce risk of coronary heart disease, and other diseases or conditions for which obesity or excess adipose tissues are risk factors.
In one embodiment, the present invention is to provide a novel method for treating or suppressing weight gain in susceptible warm-blooded animals, including humans, said method comprising administering to a subject, in need of such treatment or suppression, a therapeutically effective amount, with or without a pharmaceutical diluent excipient or carrier, of at least one compound of the general formula I: 
wherein R1 and R2 are independently selected from the group consisting of hydrogen, hydroxyl, xe2x80x94OM (M being selected from the group consisting of straight or branched C1-C4 alkyl, straight or branched C3-C4 alkenyl, straight or branched C3-C4 alkynyl) and a moiety convertible in vivo to hydroxyl;
wherein G is xe2x80x94H or xe2x80x94CH3; and
wherein R3 is a species selected from the group consisting of pyrrolidinyl, piperidino, morpholino, and NRaRb (Ra and Rb being independently hydrogen, straight or branched C1-C6 alkyl, straight or branched C3-C6 alkenyl, and straight or branched C3-C6 alkynyl).
In another embodiment, selective estrogen receptor modulator or pharmaceutically acceptable salt thereof is administered for reducing abdominal fat or reducing the accumulation of abdominal fat.
In another embodiment, sex steroid precursor (e.g. dehydroepiandrosterone, dehydroepiandrosterone sulfate, androst-5-ene-3b,17b-diol) is administered in addition to a Selective Estrogen Receptor Modulator (SERM) for the treatment of obesity or for suppressing weight gain. Human at or over fifty years of age are believed to respond well to the combination therapy, probably because precursor levels tend to undesirably decrease with age.
Thus, in that aspect, the invention provides a method for the treatment of obesity or suppression of weight gain comprising administering to a subject, in need of such suppression or treatment, a therapeutically effective amount with or without a pharmaceutical diluent or carrier, of at least one SERM and an effective amount of a at least one sex steroid precursor selected from the group consisting of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androst-5-ene-3b,17b-diol and compounds converted in vivo to any of the foregoing precursors.
In another aspect, the invention provides a method for treating or reducing the risk of developing insulin resistance comprising administering, to a subject in need of such treatment or reduction, a therapeutically effective amount of at least one SERM. In some embodiments, an effective amount of at least one sex steroid precursor selected from the group consisting of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androst-5-ene-3b,17b-diol and compounds converted in vivo to either is administered also as part of a combination therapy.
In another aspect, the invention provides a kit for the treatment of obesity having a first container which includes at least one SERM and a second container which includes at least one sex steroid precursor selected from the group consisting of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androst-5-ene-3b,17b-diol and compounds converted in vivo to either.
A pharmaceutical excipient carrier or diluent may also be provided in one or more of the containers and may include preservatives and other additives known in the art. The foregoing may also be included with any active ingredient used in any embodiment of the various inventions described herein.
As used herein, a selective estrogen receptor modulator (SERM) is a compound that either directly or through its active metabolite functions as an estrogen receptor antagonist (xe2x80x9cantiestrogenxe2x80x9d) in breast tissue, yet provides estrogen-like effect on body fat, on bone tissue and on serum cholesterol levels (i.e. by reducing serum cholesterol). Non-steroidal compounds that function as estrogen receptor antagonists in vitro or in human or rat breast tissue (especially if the compound acts as an antiestrogen on human breast cancer cells) is likely to function as a SERM. Non-steroidal antiestrogens we have tested and found to function as SERMs include EM-800, EM-652, EM-652.HCl (EM-01538) Raloxifene, Tamnoxifen, Idoxifene, Torimefene, LY 353381, LY 335563, GW 5638 and Droloxifene (described in more detail below). SERMs, in accordance with any embodiment of the invention, are preferably administered at the same dosage as known in the art when these compounds are used as antiestrogens.
Without intending to be bound by theory, it is believed that SERMs, many of which preferably have two aromatic rings linked by one to two carbon atoms, are expected to interact with the estrogen receptor by virtue of the foregoing portion of the molecule that is best recognized by the receptor. Such SERMs also have side chains which may selectively cause antagonistic properties in breast and endometrial tissues without having significant antagonistic properties in other tissues especially bone. Thus, the SERMs may desirably function as antiestrogens in the breast and endometrium while surprisingly and desirably having estrogen-like activity on body fat.
The invention also includes desirably suppressing additional weight gain or desirably providing weight reduction, even if normal weight is not achieved.
As used herein, the term obesity implies an excess of adipose tissue which leads to a weight gain. Prevention and treatment methods of the invention include the inhibition of weight gain and induction of weight loss. The invention includes the treatment of obese humans by reducing their weight to (and maintain the weight at) the normal. The invention also includes the prevention of obesity for persons who are susceptible to acquiring such disease. Patients in need of the invention herein, include those who are overweight (as compared to medically recognized norms) or at risk of becoming overweight.
SERM may also be used to lower blood triglyceride levels in accordance with the invention. For example, EM-800 (described herein) is believed effective for this purpose.
In another embodiment, novel compounds and pharmaceutical compositions for carrying out the invention are provided.
A patient in need of such treatment or reducing the risk of onset of a given disease or condition is one who has either been diagnosed with such disease or one who is susceptible to acquiring such disease. The invention is especially useful for individuals who, due to heredity, environmental factors or other recognized risk factor, are at higher risk than the general population of acquiring the conditions to which the present invention relates.
Except where otherwise stated, the preferred dosage of the active compounds of the invention is identical for both therapeutic and prophylactic purposes. The dosage for each active component discussed herein is the same regardless of the disease being treated (or prevented).
Where two are more different active agents are discussed as part of a combination therapy herein (e.g. an enzyme inhibitor and an antiandrogen), a plurality of different compounds are administered rather than a single compound having multiple activities.
Except where otherwise indicated, the term xe2x80x9ccompoundxe2x80x9d and any associated molecular structure may include any possible stereoisomers thereof, in the form of a racemic mixture or in optically active form.
Except where otherwise noted or where apparent from context, dosages herein refer to weight of active compounds unaffected by pharmaceutical excipients, diluents, carriers or other ingredients, although such additional ingredients are desirably included, as shown in the examples herein. Any dosage form (capsule, tablet, injection or the like) commonly used in the pharmaceutical industry is appropriate for use herein, and the terms xe2x80x9cexcipientxe2x80x9d, xe2x80x9cdiluentxe2x80x9d or xe2x80x9ccarrierxe2x80x9d include such non-active ingredients as are typically included, together with active ingredients in such dosage forms in the industry. For example, typical capsules, pills, enteric coatings, solid or liquid diluents or excipients, flavorats, preservatives, or the like are included.
In some embodiments, prodrugs of the active ingredients discussed herein (i.e. compounds which convert in vivo to the active ingredients) are used. Many functional groups are known in the pharmaceutical industry to convert in vivo to functional groups of the active compounds discussed herein. See, e.g., Chapter 5 xe2x80x9cDesign and Application of Prodrugsxe2x80x9d, A Textbook of Drug Design and Development, Bundgaard and Larsen, Ed., Harwood Academic Publishers GmbH (Chur, Switzerland, 1991). Prodrugs frequently can provide better bioavailability, shelf stability and/or ease of manufacture, corresponding active compounds.
All of the active ingredients used in any of the therapies discussed herein may be formulated in pharmaceutical compositions which also include one or more of the other active ingredients. Alternatively, they may each be administered separately but sufficiently simultaneous in time so that a patient eventually has elevated blood levels or otherwise enjoys the benefits of each of the active ingredients (or strategies) simultaneously. In some preferred embodiments of the invention, for example, one or more active ingredients are to be formulated in a single pharmaceutical composition. In order embodiments of the invention, a kit is provided which includes at least two separate containers wherein the contents of at least two separate containers wherein the contents of at least one container differs, in whole or in part, from the contents of at least one other container with respect to active ingredients contained therein. Two or more different containers are used in the combination therapies of the invention. Combination therapies discussed herein also include use of one active ingredient of the combination in the manufacture of a medicament for the treatment (or prevention) of the disease in question where the treatment or prevention further includes another active ingredient or strategy of the combination.
Abdominal fat is believed different from, and can occur in the absence of, overall bodily obesity. It is also believed to be more of a risk factor in heart disease. Abdominal fat responds favorably to the present invention.
Preferred SERMs of the invention, e.g., those of Formula 1 above, lack undesirable estrogenic effects in the endometrium, a very important improvement relative to SERM therapies utilized in some prior art methods.
SERMs used in the invention are believed to beneficially reduce blood triglycerides and also insulin resistance.
In preferred embodiments discussed herein, the action of SERM is augmented by DHEA or similar sex steroid precursor.
Without intending to be bound by theory, one explanation of the synergy obtained by combining SERMs and precursors could be at least partial differences in their mechanisms of action. DHEA, for example, appears to increase food metabolism without suppressing appetite. EM-652.HCl, a SERM, appears to suppress food intake.